Cyclopropyl-alanine aryl/alkylsulfide/sulfonyl-terminated amino-diol compounds for treatment of hypertension

ABSTRACT

Compounds characterized generally as cyclopropyl alanine aryl/alkylsulfide/sulfonyl-terminated amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of the formula ##STR1## wherein R 1  is selected from isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl, naphthyl, fluoronaphthyl, chloronaphthyl, fluoronapthylmethyl and chloronaphthylmethyl; wherein x is zero or two; wherein R 2  is selected from hydrido, methyl, ethyl and phenyl; wherein R 3  is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R 5  is cyclopropylmethyl wherein R 7  is cyclohexylmethyl; and wherein R 8  is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl.

FIELD OF THE INVENTION

Renin-inhibiting compounds are known for control of hypertension. Ofparticular interest herein are compounds useful as renin inhibitingagents.

BACKGROUND OF THE INVENTION

Renin is a proteolytic enzyme produced and secreted into the bloodstreamby the juxtaglomerular cells of the kidney. In the bloodstream, renincleaves a peptide bond in the serum protein angiotensinogen to produce adecapeptide known as angiotensin I. A second enzyme known as angiotensinconverting enzyme, cleaves angiotensin I to produce the octapeptideknown as angiotensin II. Angiotensin II is a potent pressor agentresponsible for vasoconstriction and elevation of cardiovascularpressure. Attempts have been made to control hypertension by blockingthe action of renin or by blocking the formation of angiotensin II inthe body with inhibitors of angiotensin I converting enzyme.

Classes of compounds published as inhibitors of the action of renin onangiotensinogen include renin antibodies, pepstatin and its analogs,phospholipids, angiotensinogen analogs, pro-renin related analogs andpeptide aldehydes.

A peptide isolated from actinomyces has been reported as an inhibitor ofaspartyl proteases such as pepsin, cathepsin D and renin [Umezawa et al,in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. This peptide, known aspepstatin, was found to reduce blood pressure in vivo after theinjection of hog renin into nephrectomized rats [Gross et al, Science,175, 656 (1971)]. Pepstatin has the disadvantages of low solubility andof inhibiting acid proteases in addition to renin. Modified pepstatinshave been synthesized in an attempt to increase the specificity forhuman renin over other physiologically important enzymes. While somedegree of specificity has been achieved, this approach has led to ratherhigh molecular weight hepta- and octapeptides [Boger et al, Nature, 303,81 (1983)]. High molecular weight peptides are generally consideredundesirable as drugs because gastrointestinal absorption is impaired andplasma stability is compromised.

Short peptide aldehydes have been reported as renin inhibitors [Kokubuet al, Biochim, Biophys. Res. Commun., 118, 929 (1984); Castro et al,FEBS Lett., 167, 273 (1984)]. Such compounds have a reactive C-terminalaldehyde group and would likely be unstable in vivo.

Other peptidyl compounds have been described as renin inhibitors. EPAppl. #128,762, published Dec. 18, 1984, describes dipeptide andtripeptide glyco-containing compounds as renin inhibitors [also seeHanson et al, Biochm. Biophys. Res. Comm., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published May 14, 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #186,977published Jul. 9, 1986 describes renin-inhibiting compounds containingan alkynyl moiety, specifically a propargyl glycine moiety, attached tothe main chain between the N-terminus and the C-terminus, such asN-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-DL-propargylglycylamino]-3(S)-hydroxy-6-methylheptanoyl]-L-isoleucinol.EP Appl. #189,203, published Jul. 30, 1986, describespeptidyl-aminodiols as renin inhibitors. EP Appl. #200,406, publishedDec. 10, 1986, describes alkylnaphthylmethylpropionyl-histidylaminohydroxy alkanoates as renin inhibitors. EP Appl. #216,539,published Apr. 1, 1987, describes alkylnaphthylmethylpropionyl aminoacylaminoalkanoate compounds as renin inhibitors orally administered fortreatment of renin-associated hypertension. PCT Application No. WO87/04349, published Jul. 30, 1987, describes aminocarbonyl aminoacylhydroxyether derivatives having an alkylamino-containing terminalsubstituent and which are described as having renin-inhibiting activityfor use in treating hypertension. EP Appl. #300,189 published Jan. 25,1989 describes amino acid monohydric derivatives having analkylamino-alkylamino N-terminus and a β-alanine-histidine orsarcosyl-histidine attached to the main chain between the N-terminus andthe C-terminus, which derivatives are mentioned as useful in treatinghypertension. U.S. Pat. No. 4,902,706 which issued Feb. 13, 1990describes a series of histidineamide-containing aminoalkylaminocarbonyl-H-terminal aminodiol derivatives for use as renininhibitors. U.S. Pat. No. 5,032,577 which issued Jul. 16, 1991 describesa series of histidineamide-aminodiol-containing renin inhibitors.

Several classes of sulfonyl-containing amino-diol renin-inhibitorscompounds are known. For example, EP #229,667 published Jul. 22, 1987describes generally alkylsulfonyl histidineamide amino diolC-terminated-alkyl compounds as renin inhibitors. Australian PatentApplication #30797/89 published Sep. 7, 1989 describes alkylsulfonylhistineamide amino diol C-terminated-alkyl compounds as renininhibitors, such as(S)-α-[(S)-α-[(t-butyl-sulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4,4-dimethylpentyl]-imidazole-4-propionamideand(S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S,4RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylhexyl]imidazole-4-propionamide.U.S. Pat. No. 4,914,129 issued Apr. 3, 1990 describes sulfone-containingamino-hydroxyvaleryl compounds for use as antihypertensive agents, suchas the compoundsN-[2(S)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamideandN-[2(R)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamide.EP #416,373 published Mar. 13, 1991 describes alkylsulfonylhistidineamide amino diol compounds as renin-inhibitors, such as(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazol-4-propionamideand(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3R/S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxybutyl]imidazol-4-propionamide.

DESCRIPTION OF THE INVENTION

Cycloalkylalkyl alanine aryl/alkylsulfonyl-terminated amino diolcompounds, having utility as renin inhibitors for treatment ofhypertension in a subject, constitute a family of compounds of generalFormula I: ##STR2## wherein R¹ is a group selected from alkyl,trifluoromethyl, cycloalkyl, cycloalkylalkyl, aryl, haloaryl, aralkyland haloaralkyl; wherein x is a number selected from zero, one and two;wherein R² is selected from hydrido and alkyl; wherein R³ is a groupselected from hydrido, cycloalkylalkyl, aralkyl and haloaralkyl; whereineach of R⁴ and R⁶ is a group independently selected from hydrido andmethyl; wherein R⁵ is selected from cycloalkylalkyl groups containingfrom three to about twelve carbon atoms; wherein R⁷ is a group selectedfrom alkyl, cycloalkylalkyl and aralkyl; wherein R⁸ is a group selectedfrom hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyland haloalkenyl; and wherein any one of said R¹ through R⁸ groups havinga substitutable position may be substituted with one or more groupsselected from alkyl, hydroxy, alkoxy and alkenyl.

A preferred family of compounds consists of compounds of Formula Iwherein R¹ is selected from alkyl, trifluoromethyl, cycloalkyl,cycloalkylalkyl, phenyl, halophenyl, phenylalkyl, halophenylalkyl,naphthyl, halonaphthyl, naphthylaklyl and halonaphthylalkyl; wherein xis a number selected from zero, one and two; wherein R² is selected fromhydrido and alkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl andcycloheptylethyl; wherein R⁷ is selected from cyclohexylmethyl andbenzyl, either one of which may be substituted with one or more groupsselected from alkyl, hydroxy and alkoxy; and wherein R⁸ is selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl.

A more preferred family of compounds consists of compounds of Formula Iwherein R¹ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl,chlorophenyl, trifluoromethylphenyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, fluorophenylpropyl, chlorobenzyl,chlorophenylethyl, chlorophenylpropyl, naphthyl, fluoronaphthyl,chloronaphthyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein x is a number selected from zero, one andtwo; wherein R² is selected from hydrido, methyl, ethyl and n-propyl;wherein R³ is selected from hydrido, cyclohexylmethyl, benzyl,phenylethyl, fluorobenzyl, fluorophenylethyl, chlorobenzyl,chlorophenylethyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyland chloronaphthylmethyl; wherein each of R⁴ and R⁶ is independentlyselected from hydrido and methyl; wherein R⁵ is selected fromcyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl andcyclohexylethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl,cyclobutylmethyl, cyclohexylmethyl, allyl and vinyl.

An even more preferred family of compounds consists of compounds FormulaI wherein R¹ is selected from methyl, ethyl, n-propyl, isopropyl,benzyl, phenethyl, phenyl, fluorophenyl, chlorophenyl,trifluoromethylphenyl, benzyl, phenylethyl, phenylpropyl, fluorobenzyl,fluorophenylethyl, fluorophenylpropyl, chlorobenzyl, chlorophenylethyl,chlorophenylpropyl, naphthyl, fluoronaphthyl, chloronaphthyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein x is zero or two; wherein R² is selectedfrom hydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl,cyclohexylethyl and cyclohexylpropyl; wherein R⁷ is cyclohexylmethyl;and wherein R⁸ is selected from ethyl, n-propyl, n-butyl, isobutyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl.

A highly preferred family of compounds consists of compounds of FormulaI wherein R¹ is selected from isopropyl, isobutyl, sec-butyl,tert-butyl, phenyl, fluorophenyl, chlorophenyl, benzyl, fluorobenzyl,chlorobenzyl, naphthyl, fluoronaphthyl, chloronaphthyl,fluoronaptthylmethyl and chloronaphthylmethyl; wherein x is zero or two;wherein R² is selected from hydrido, methyl, ethyl and phenyl; whereinR³ is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl,chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is selected fromcyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl; wherein R⁷ iscyclohexylmethyl; and wherein R⁸ is selected from n-propyl, isobutyl,cyclopropyl, cyclopropylmethyl, allyl and vinyl.

The term "hydrido" denotes a single hydrogen atom (H). This hydridogroup may be attached, for example, to an oxygen atom to form a hydroxylgroup; or, as another example, one hydrido group may be attached to acarbon atom to form a >CH-- group; or, as another example, two hydridogroups may be attached to a carbon atom to form a --CH₂ -- group. Wherethe term "alkyl" is used, either alone or within other terms such s"hydroxylalkyl", the term "alkyl" embraces linear or branched radicalshaving one to about twenty carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred alkyl radicals are "lower alkyl"radicals having one to about ten carbon atoms. Most preferred are loweralkyl radicals having one to about six carbon atoms. The term"cycloalkyl" embraces cyclic radicals having three to about ten ringcarbon atoms, preferably three to about six carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The terms "alkylol"and "hydroxyalkyl" embrace linear or branched alkyl groups having one toabout ten carbon atoms any one of which may be substituted with one ormore hydroxyl groups. The term "alkenyl" embraces linear or branchedradicals having two to about twenty carbon atoms, preferably three toabout ten carbon atoms, and containing at least one carbon-carbon doublebond, which carbon-carbon double bond may have either cis or transgeometry within the alkenyl moiety. The term "alkynyl" embraces linearor branched radicals having two to about twenty carbon atoms, preferablytwo to about ten carbon atoms, and containing at least one carbon-carbontriple bond. The terms "alkoxy" and "alkoxyalkyl" embrace linear orbranched oxy-containing radicals each having alkyl portions of one toabout ten carbon atoms, such as methoxy group. The term "alkoxyalkyl"also embraces alkyl radicals having two or more alkoxy groups attachedto the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylgroups. Preferred aryl groups are those consisting of one, two, or threebenzene rings. The term "aryl" embraces aromatic radicals such asphenyl, naphthyl and biphenyl. The term "aralkyl" embracesaryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl. The terms"benzyl" and "phenylmethyl" are interchangeable. Each of the termssulfide, sulfinyl, and "sulfonyl", whether used alone or linked to otherterms, denotes, respectively, the divalent radicals ##STR3## The term"alkenylalkyl" denotes a radical having a double-bond unsaturation sitebetween two carbons, and which radical may consist of only two carbonsor may be further substituted with alkyl groups which may optionallycontain additional double-bond unsaturation. For any of the foregoingdefined radicals, preferred radicals are those containing from one toabout fifteen carbon atoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

Also included in the family of compounds of Formula I are isomericforms, including diastereoisomers.

Compounds of Formula I would be useful to inhibit enzymatic conversionof angiotensinogen to angiotensin I. When administered orally, acompound of Formula I would be expected to inhibit plasma renin activityand, consequently, lower blood pressure in a mammalian subject (e.g., ahuman subject). Thus, compounds of Formula I would be therapeuticallyuseful in methods for treating hypertension by administering to ahypertensive subject a therapeutically-effective amount of a compound ofFormula I. The phrase "hypertensive subject" means, in this context, amammalian subject suffering from or afflicted by the effects ofhypertension, or susceptible to a hypertensive condition if not treatedto prevent or control such hypertension. ##STR4##

A suitably protected amino aldehyde 1 is treated with a Grignard reagentor other organometallic reagent, preferably vinylmagnesium bromide, toobtain the vinyl carbinol 2. This material, suitably protected, isoxidized, preferably with ozone, followed by dimethyl sulfide or zinctreatment, to give intermediate 3. The preceeding process is exemplifiedin Hanson et al, J. Org. Chem., 50, 5399 (1985). This aldehyde isreacted with an organometallic reagent such as isobutylamagnesiumchloride to give intermediate 4. Other suitable organometallic reagentsinclude ethylmagnesium bromide, vinylmagnesium bromide,cyclopropylmagnesium bromide, and allylmagnesium bromide, but thechoices are not limited to these reagents. After the formation of 4,further transformation of the added side chain is permitted, beforegoing on the next depicted step. For example, the compound 4 derivedfrom the addition of allylmagnesium bromide may be cyclopropanated viadiazomethane and rhodium acetate, to give a cyclopropylmethyl sidechain. Compound 4 is deprotected then coupled, using standardamide/peptide coupling methodology to protectedcycloalkylalkyl-containing amino acid derivatives 5 to give compound 6.These standard coupling procedures such as the carbodiimide, activeester (N-hydroxysuccinimide), and mixed carbonic anhydride methods areshown in Benoiton et al, J. Org. Chem., 48, 2939 (1983) and Bodansky etal, "Peptide Synthesis", Wiley (1976). Cyclopropylemethyl-containingamino acid derivatives may be prepared by cyclopropanation ofallylglycine using procedures such as found in Borbruggen, TetrahedronLetters, 9, 629 (1975). Intermediate 6 is then deprotected, then coupledto intermediate 7 or 11 or 12 using the standard amide/peptide couplingmethodology, to give compounds of Formula I. Suitable protecting groupsmay be selected from among those reviewed by R. Geiger in "ThePeptides", Academic Press, New York vol. 2 (1979). For example, P₁ or P₃may by Boc or Cbz; P₂ may be a typical oxygen protective group such asacetyl or t-butyldimethylsilyl. ##STR5##

Intermediate 7 may be prepared according to Synthetic Scheme 2. Michaeladdition of a suitable thiol 9 to a suitable acrylic acid 8 in thepresence of base catalysts such as sodium hydride, triethyl amine orbenzyltrimethylammonium hydroxide, afforded α,β di-substitutedthio-propionic acid alkyl esters 10. In the case of R² =H, a suitablemalonic acid dialkyl ester is hydrolyzed to a mono ester, followed byconcomitant decarboxylative dehydration to provide α substituted acrylicacid alkyl ester. Compound 10 is converted into its correspondingsulfone acid 7 via base hydrolysis, followed by oxidation with potassiumperoxomonosulfate or perbenzoic acid. Compound 10 may also be convertedinto its corresponding thio-propionic acid 11 via base hydrolysis.Compound 11 then is further converted into its corresponding sulfoxideacid 12 via 3-chloroperbenzoic acid oxidation.

Abbreviations: P₁ is an N-protecting group; P₂ is H or an oxygenprotecting group; P₃ is an N-protecting group.

The following Steps 1-8 constitute specific exemplification of methodsto prepare starting materials and intermediates embraced by theforegoing generic synthetic schemes. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of Steps 1-8. All temperatures expressed are in degreesCentigrade. Compounds of Examples 1-3 may be prepared by using theprocedures described in the following Steps 1-8:

Step 1: Preparation of(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal

Ozone/oxygen was bubbled at -70° C. into a solution of(3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene(2.55 g, 8.0 mmol) [prepared by the method of Hanson, et al., J. Org.Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deepblue color persisted. Oxygen was introduced until the blue colorcompletely faded, then 3.0 mL of Me₂ S was added and the solution wasallowed to warm to 0°-5° C. and stand overnight. The solvent was removedat 0° C. under vacuum yielding the title compound as a thick yellow oilwhich was used in the following step without purification.

Step 2: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane

The oil prepared in Step 1 was dissolved under nitrogen in 100 mL of dryTHF and cooled to -70° C. To this solution was added 13 mL (26 mmol) ofa 2.0M solution of isobutylmagnesium chloride in ether and the stirredmixture was allowed to warm to room temperature and stir for 2 hrs.After decomposition with MeOH/H₂ O the mixture was diluted with ether,washed with saturated NH₄ Cl solution twice, then dried and the solventsstripped off under vacuum. The residue was allowed to stand overnight in80% MeOH--H₂ O containing excess ammonium hydroxide. The MeOH wasstripped off and the mixture was extracted with ether. These extractswere combined, washed with water, dilute KHSO₄, then dried andevaporated to give 2.36 g of a yellow glass which crystallized from 50mL of pentane on standing overnight. The yellow-white powder obtainedwas recrystallized from etherhexane and furnished the title compound(0.41 g) as white, hairy needles, mp 134°-136° C., Rf (ether): singlespot, 0.6. By chromatography of the mother liquors and crystallizationof the appropriate fractions, an additional 0.22 g of product, mp138°-139° C., was obtained.

Anal: Calcd. for C₁₉ H₃₁ NO₄ (337.45): C, 67.62; H, 9.26; N, 4.15.Found: C, 67.51; H, 9.43; N, 4.24.

Step 3: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The diol of Step 2, 0.27 g, was reduced in MeOH with 60 psi H₂ at 60° C.in 3 hours using 5% Rh/C catalyst. After filtering, the solvent wasstripped off and the white crystals were recrystallized from CH₂ Cl₂-hexane to furnish tiny needles of the title compound, 0.19 g, mp126°-128° C.; further recrystallization gave mp 128.5°-129.5° C. Rf(ether): single spot, 0.8.

Anal: Calcd. for C₁₉ H₃₇ NO₄ (343.50): C, 66.43; H, 10.86, N, 4.08.Found: C, 66.43; H, 11.01; N, 4.03.

Step 4: Preparation of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 3 (10 g) was dissolved 6.9N HCl in dioxane(300 mL). The mixture was stirred for 30 minutes at room temperature.The solvent was removed in vacuo and to the residue was added 5% aqueoussodium hydroxide (30 mL) until a pH of 14 was obtained. This mixture wasextracted with ether and the ether extract was washed with water andbrine, then the solvent was evaporated to give the title compound (7.3g, 100% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₁₄ H₂₉ NO₂ : C, 69.07; H, 12.01; N, 5.78. Found: C,69.19; H, 12.34; N, 5.78.

Step 5: Preparation ofN-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-2R*-[(1,1-dimethylethoxy)carbonyl]amino]-4-penteneamide

1-methylpiperidine (286 mg, 2.88 mmol) was added to a stirred solutionof L-t-Boc-allylglycine (620 mg, 2.88 mmol) in methylene chloride (10mL). After the reaction flask was cooled to -10° C., isobutylchloroformate (393 mg, 2.88 mmol) was added, and the reaction wasstirred for 5 min at -10° C. whereupon the title compound of Step 4 (700mg, 2.88 mmol) in 2:1 methylene chloride:tert-butanol (10 ml) wasintroduced. The solution was allowed to warm to 0° C. over a 30 minperiod and was maintained at 0° C. for 15 hours. The reaction mixturewas evaporated to dryness and then redissolved in ethyl acetate. Thiswas washed successively with 1N citric acid, saturated sodiumbicarbonate, water and brine. The solution was dried (MgSO₄) andevaporated. The crude product was purified by flash chromatography onsilica gel, eluting with 50:25:25 CH₂ Cl₂ :Hex:Et₂ O to give pure titlecompound as white solid (126 mg, 46% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Step 6: Preparation ofN-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-αR*-[(1,1-dimethylethoxy)carbonyl]aminocyclopropanpropanamide

To the title compound of Step 5 (300 mg, 0.68 mmol) and Pd(OAc)₂ (2 mg)in ether (3 ml) an ethereal CH₂ N₂ solution (10 ml, prepared from 412 mgN-nitroso-N-methyl urea) was added dropwise at 0° C. with continuousstirring for 40 min. Glacial acetic acid (1 ml) was introduced to removeexcess CH₂ N₂. The reaction mixture was washed successively with water,saturated sodium bicarbonate and brine. The solution was dried (MgSO₄)and evaporated (280 mg, 90% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₂₅ H₄₆ N₂ O₅ : C, 66.04; H, 10.20; N, 6.16. Found: C,65.81; H, 10.26; N, 6.02.

Step 7: Preparation ofαR*-amino-N-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-cyclopropanpropanamide

The title compound of Step 6 (280 mg, 0.67 mmol) was dissolved inmethylene chloride (2 ml) and cooled to 0° C. To the reaction mixturetrifluoroacetic acid (4 ml) was added quickly and continuous stirringfor 1 hr. The reaction mixture was then concentrated and the residuetreated with excess aqueous NaHCO₃, extracted with ethyl acetate (3×10ml). The combined organic phase was dried (Na₂ SO₄) and thenconcentrated to afford the title compound (120 mg, 55% yield).

¹ H and ¹³ C NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₂₀ H₃₈ N₂ O₃ +0.2 H₂ O Calc., C:67.08, H:10.81,N:7.82, Found:C:67.09, H:10.55, N:7.70.

Step 8: Preparation of R,S-2-Benzyl-3-tertbutylsulphonyl-proionic acid

The title compound of Step 8 was prepared by procedures described inStep 8(a) to (d), below:

Step (a): Preparation of α-benzylacrylic acid ethyl ester:

A mixture of 8.5 g of KOH in 100 ml of ethanol was added at roomtemperature to 40 g of benzylmalonic acid diethyl ester in 80 ml ofethanol. The mixture was stirred overnight at room temperature, thenconcentrated by evaporation, thereafter 14 ml of water was added andthen the mixture was acidified in an ice bath with 12.6 ml ofconcentrated hydrochloric acid. Partitioning between water and ether wascarried out, the organic phase was dried and the ether was distilledoff. Then, 26 ml of pyridine, 1.22 g of piperidine and 3.56 g ofparaformaldehyde were added to the residue. The mixture was heated in anoil bath (130°) for 90 minutes, cooled, 440 ml of water was added andextraction was carried out 3 times with 150 ml of n-hexane. The combinedorganic phases were washed alternatively with water, 1N HCl, water,saturated NaHCO₃ solution and brine. The solution was dried (MgSO₄) andevaporated to give the title compound as colorless oil (26 g, 85% yield)

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Step (b): Preparation of 2-benzyl-3-tert.-butylthiopropionic acid ethylester:

4.0 g of α-benzylacrylic acid ethyl ester was dissolved in 40 ml of THFand reacted at room temperature with a mixture of 2.39 ml oftert.-butylmercaptan and 459 mg of sodium hydride dispersion (60% inoil). The mixture was stirred at room temperature for 5 hours, pouredinto 1N hydrochloric acid and extracted with ethyl acetate. The extractswere dried and concentrated by evaporation. The residue was purified byflash chromatography on silica gel, eluting with hexane-ethyl acetate(8:1). Colorless oil (4 g, 68% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₁₆ H₂₄ O₂ S: C, 68.53; H, 8.63. Found: C, 68.10; H,8.47.

Step (c): Preparation of 2-benzyl-3-tert.-butylthio-propionic acid:

400 mg of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester wasdissolved in 1.5 ml of methanol and then reacted with 5 ml of 2Npotassium hydroxide solution. The mixture was stirred overnight at roomtemperature and concentrated by evaporation. The residue was dilutedwith water and washed with ether. The aqueous layer was acidified to pH3 with 2N HCl, and then evaporated to give the title compound (280 mg,78% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Step (d): Preparation of 2-benzyl-3-tert.-butylsulphonylpropionic acid:

280 mg of 2-benzyl-3-tert.-butylthio-propionic acid was dissolved in 5ml of methanol and, while cooling with ice, 1 g of potassiumperoxomonosulfate in 4 ml of water was added and the whole was stirredovernight at room temperature. The solution was diluted with water andextracted with methylene chloride, and the extracts were dried andconcentrated by evaporation (260 mg, 82% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure. Anal:calcd. for C₁₄ H₂₀ O₄ S: C, 59.13; H, 7.09. Found: C, 59.39; H, 7.08.

The following working Examples are provided to illustrate synthesis ofCompounds 1-36 of the present invention and are not intended to limitthe scope thereof. Those skilled in the art will readily understand thatknown variations of the conditions and processes of the followingpreparative procedures can be used to prepare the compounds of theExamples. All temperatures expressed are in degrees Centigrade.

EXAMPLE 1 ##STR6##

The acid of Step 8 (143 mg, 0.50 mmol) was dissolved at room temperaturein a mixture of dimethylformamide (2 mL) and pyridine (0.2 mL) and tothis solution was added N,N'-disuccinimidyl carbonate (119 mg, 0.46mmol) and 4-dimethylaminopyridine (5 mg). The mixture was stirred for 3hours, and then the title amine of Step 7 (150 mg, 0.42 mmol) was added,followed by diisopropyl ethylamine (80 μL). This mixture was allowed tostir for 16 hours. The solvent was then evaporated and the residuedissolved in ethyl acetate (15 mL). The mixture was washed successivelywith water, 0.5M citric acid saturated sodium bicarbonate and brine,then dried over sodium sulfate and the solvent evaporated. The residuewas purified by flash chromatography on silica gel, eluting withmethylene chloride:methanol (20:1) to give the title compound as a whitepowder (50 mg, 19% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₃₄ H₅₆ N₂ O₆ S: C, 65.77; H, 9.09; N, 4.51. Found: C,65.59; H, 9.03; N, 4.54.

EXAMPLE 2 ##STR7##

The acid of Step 8 (C) (137 mg, 0.54 mmol) was dissolved at roomtemperature in a mixture of dimethylformamide (3 mL) and pyridine (0.6mL) and to this solution was added N,N'-disuccinimidyl carbonate (127mg, 0.5 mmol) and 4-dimethylaminopyridine (6 mg). The mixture wasstirred for 3 hours, and then the title amine of Step 7 (160 mg, 0.45mmol) was added, followed by diisopropyl ethylamine (87 μL). Thismixture was allowed to stir for 16 hours. The solvent was thenevaporated and the residue dissolved in ethyl acetate (15 mL). Themixture was washed successively with water, 0.5M citric acid, saturatedsodium bicarbonate and brine, then dried over sodium sulfate and thesolvent evaporated to give the title compound as a white powder (220 mg,83% yield).

¹ H NMR: 300 MHz spectrum consistent with proposed structure.

Anal: calcd. for C₃₄ H₅₆ N₂ O₄ S+0.7 H₂ O: C, 67.89; H, 9.62; N, 4.66.Found: C, 67.71; H, 9.64; N, 4.73.

EXAMPLE 3 ##STR8##

3-(Phenylsulfonyl)propionic acid (107 mg, 0.5 mmol) is dissolved inbenzene (6 ml) at room temperature. To this, oxalyl chloride (63 mg, 0.5mmol) and catalytic amount of dimethylformamide are added, and themixture is allowed to stir for 2 hours. The solvent is then evaporated,and the residue is dissolved in methylene chloride (12 ml) and the titleamine of Step 7 (177 mg, 0.5 mmol) is added, followed by1-methylpiperidine (50 mg, 0.5 mmol). This mixture is allowed to stirfor 16 hours. The solvent is then evaporated and the residue isdissolved in ethyl acetate (30 ml), and washed with water, 1N HCl,saturated sodium bicarbonate and brine, then dried (Na₂ SO₄) andevaporated to give the title compound.

Compounds #4-36, as shown in Table I below, may be synthesized byreference to the foregoing specific and general procedures for preparingcompounds of Formula I.

                                      TABLE I                                     __________________________________________________________________________    Example Compound No.                                                                      Structure                                                         __________________________________________________________________________     4                                                                                         ##STR9##                                                          5                                                                                         ##STR10##                                                         6                                                                                         ##STR11##                                                         7                                                                                         ##STR12##                                                         8                                                                                         ##STR13##                                                         9                                                                                         ##STR14##                                                        10                                                                                         ##STR15##                                                        11                                                                                         ##STR16##                                                        12                                                                                         ##STR17##                                                        13                                                                                         ##STR18##                                                        14                                                                                         ##STR19##                                                        15                                                                                         ##STR20##                                                        16                                                                                         ##STR21##                                                        17                                                                                         ##STR22##                                                        18                                                                                         ##STR23##                                                        19                                                                                         ##STR24##                                                        20                                                                                         ##STR25##                                                        21                                                                                         ##STR26##                                                        22                                                                                         ##STR27##                                                        23                                                                                         ##STR28##                                                        24                                                                                         ##STR29##                                                        25                                                                                         ##STR30##                                                        26                                                                                         ##STR31##                                                        27                                                                                         ##STR32##                                                        28                                                                                         ##STR33##                                                        29                                                                                         ##STR34##                                                        30                                                                                         ##STR35##                                                        31                                                                                         ##STR36##                                                        32                                                                                         ##STR37##                                                        33                                                                                         ##STR38##                                                        34                                                                                         ##STR39##                                                        35                                                                                         ##STR40##                                                        36                                                                                         ##STR41##                                                        __________________________________________________________________________

BIOLOGICAL EVALUATION Human Renin Inhibition in vitro

Compounds of Formula I were evaluated as inhibitors of human renin in anin vitro assay, as follows: This human renin inhibition test has beenpreviously described in detail [Papaioannou et al., Clinical andExperimental Hypertension, A7(9), 1243-1257 (1985)]. Human renin wasobtained from the National Institute for Biological Standards, London.An incubation mixture was prepared containing the following components:in a total volume of 0.25 mL: 100 mM Tris-acetate buffer at pH 7.4,25×10⁻⁶ Goldblatt units of renin, 0.05 mL of plasma from humanvolunteers taking oral contraceptives, 6.0 mM Na-EDTA, 2.4 mMphenylmethyl sulfonyl fluoride, 1.5 mM 8-hydroxyquinoline, 0.4 mg/mLbovine serum albumin (BSA), and 0.024 mg/mL neomycin sulfate. Thismixture was incubated for two hours at 37° C. in the presence or absenceof renin inhibitors. The produced angiotensin I was determined byradioimmunoassay (New England Nuclear kit). Test compounds to be assayedwere dissolved in DMSO and diluted with 100 mM Tris-acetate buffer at pH7.4 containing 0.5% BSA to the appropriate concentration. The finalconcentration of organic solvent in the reaction mixture was less than1%. Control incubations at 37° C. were used to correct for effects oforganic solvent on renin activity. The in vitro enzymatic conversion ofangiotensinogen to angiotensin I was inhibited by test compounds of theinvention as indicated in Table II, below:

                  TABLE II                                                        ______________________________________                                        Human Renin in vitro                                                          Inhibition Data                                                               Compound Example #                                                                            IC.sub.50 Human Renin (nM)                                    ______________________________________                                        Example 1       0.3                                                           Example 2       2.7                                                           ______________________________________                                    

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 400 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 200 mg of active compound per unit dosage form. Most preferred isa dosage form containing from about 3 mg to about 100 mg of activecompound per unit dose.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A compound of Formula I: ##STR42## wherein R¹ isselected from the group consisting of alkyl, trifluoromethyl,cycloalkyl, cycloalkylalkyl, aryl, haloaryl, aralkyl and haloaralkyl;wherein x is a number selected from the group consisting of zero, oneand two; wherein R² is selected from the group consisting of hydrido andalkyl; wherein R³ is selected from the group consisting of hydrido,cycloalkylalkyl, aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ isindependently selected from the group consisting of hydrido and methyl;wherein R⁵ is cyclopropylmethyl; wherein R⁷ is selected from the groupconsisting of alkyl, cycloalkylalkyl and aralkyl; wherein R⁸ is selectedfrom the group consisting of hydrido, alkyl, hydroxyalkyl, cycloalkyl,cycloalkylalkyl, alkenyl and haloalkenyl; and wherein any one of said R¹through R⁸ groups having a substitutable position may be substitutedwith one or more groups selected from the group consisting of alkyl,hydroxy, alkoxy and alkenyl.
 2. Compound of claim 1 wherein R¹ isselected from the group consisting of alkyl, trifluoromethyl,cycloalkyl, cycloalkylalkyl, phenyl, halophenyl, phenylalkyl,halophenylalkyl, naphthyl, halonaphthyl, naphthylaklyl andhalonaphthylalkyl; wherein x is a number selected from the groupconsisting of zero, one and two; wherein R² is selected from the groupconsisting of hydrido and alkyl; wherein R³ is selected from the groupconsisting of hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from the group consisting of hydrido and methyl;wherein R⁵ is cyclopropylmethyl; wherein R⁷ is selected from the groupconsisting of cyclohexylmethyl and benzyl, either one of which may besubstituted with one or more groups selected from the group consistingof alkyl, hydroxy and alkoxy; and wherein R⁸ is selected from the groupconsisting of hydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,alkenyl and haloalkenyl.
 3. Compound of claim 2 wherein R¹ is selectedfrom the group consisting of methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, phenyl,fluorophenyl, chlorophenyl, trifluoromethylphenyl, benzyl, phenylethyl,phenylpropyl, fluorobenzyl, fluorophenylethyl, fluorophenylpropyl,chlorobenzyl, chlorophenylethyl, chlorophenylpropyl, naphthyl,fluoronaphthyl, chloronaphthyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein x is a numberselected from zero, one and two; wherein R² is selected from the groupconsisting of hydrido, methyl, ethyl and n-propyl; wherein R³ isselected from the group consisting of hydrido, cyclohexylmethyl, benzyl,phenylethyl, fluorobenzyl, fluorophenylethyl, chlorobenzyl,chlorophenylethyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyland chloronaphthylmethyl; wherein each of R⁴ and R⁶ is independentlyselected from the group consisting of hydrido and methyl; wherein R⁵ iscyclopropylmethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl.
 4. Compound of claim 3 wherein R¹ is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, benzyl, phenethyl,phenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl, benzyl,phenylethyl, phenylpropyl, fluorobenzyl, fluorophenylethyl,fluorophenylpropyl, chlorobenzyl, chlorophenylethyl, chlorophenylpropyl,naphthyl, fluoronaphthyl, chloronaphthyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein x is zero or two;wherein R² is selected from the group consisting of hydrido, methyl,ethyl and n-propyl; wherein R³ is selected from the group consisting ofhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is cyclopropylmethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from the group consisting of ethyl, n-propyl, n-butyl,isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl.5. Compound of claim 4 wherein R¹ is selected from the group consistingof isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, fluorophenyl,chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl, naphthyl,fluoronaphthyl, chloronaphthyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein x is zero or two; wherein R² is selectedfrom the group consisting of hydrido, methyl, ethyl and phenyl; whereinR³ is selected from the group consisting of hydrido, cyclohexylmethyl,benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is cyclopropylmethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from the group consisting of n-propyl, isobutyl, cyclopropyl,cyclopropylmethyl, allyl and vinyl.
 6. Compound of claim 5 selected fromcompounds, their tautomers, and the pharmaceutically-acceptable estersthereof, of the group consisting of ##STR43##
 7. Compound of claim 6which is N-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-a-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide.8. Compound of claim 6 which isN-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-a-[[(1,1-dimethylethyl)thio]methyl]benzenepropanamide.9. Compound of claim 6 which isN-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-αR*-[[1-oxo-3-(phenylsulfonyl)propyl]amino]cyclopropanepropanamide.10. A pharmaceutical composition comprising a therapeutically-effectiveamount of a renin-inhibiting compound and a pharmaceutically-acceptablecarrier or diluent, said renin-inhibiting compound selected from afamily of compounds of Formula I: ##STR44## wherein R¹ is selected fromthe group consisting of alkyl, trifluoromethyl, cycloalkyl,cycloalkylalkyl, aryl, haloaryl, aralkyl and haloaralkyl; wherein x is anumber selected from the group consisting of zero, one and two; whereinR² is selected from the group consisting of hydrido and alkyl; whereinR³ is selected from the group consisting of hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is independentlyselected from the group consisting of hydrido and methyl; wherein R⁵ iscyclopropylmethyl; wherein R⁷ is selected from the group consisting ofalkyl, cycloalkylalkyl and aralkyl; wherein R⁸ is selected from thegroup consisting of hydrido, alkyl, hydroxyalkyl, cycloalkyl,cycloalkylalkyl, alkenyl and haloalkenyl; and wherein any one of said R¹through R⁸ groups having a substitutable position may be substitutedwith one or more groups selected from the group consisting of alkyl,hydroxy, alkoxy and alkenyl.
 11. The composition of claim 10 wherein R¹is selected from the group consisting of alkyl, trifluoromethyl,cycloalkyl, cycloalkylalkyl, phenyl, halophenyl, phenylalkyl,halophenylalkyl, naphthyl, halonaphthyl, naphthylaklyl andhalonaphthylalkyl; wherein x is a number selected from the groupconsisting of zero, one and two; wherein R² is selected from the groupconsisting of hydrido and alkyl; wherein R³ is selected from the groupconsisting of hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from the group consisting of hydrido and methyl;wherein R⁵ is cyclopropylmethyl; wherein R⁷ is selected from the groupconsisting of cyclohexylmethyl and benzyl, either one of which may besubstituted with one or more groups selected from the group consistingof alkyl, hydroxy and alkoxy; and wherein R⁸ is selected from the groupconsisting of hydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl,alkenyl and haloalkenyl.
 12. The composition of claim 11 wherein R¹ isselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,phenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl, benzyl,phenylethyl, phenylpropyl, fluorobenzyl, fluorophenylethyl,fluorophenylpropyl, chlorobenzyl, chlorophenylethyl, chlorophenylpropyl,naphthyl, fluoronaphthyl, chloronaphthyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein x is a numberselected from the group consisting of zero, one and two; wherein R² isselected from the group consisting of hydrido, methyl, ethyl andn-propyl; wherein R³ is selected from the group consisting of hydrido,cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl,chlorobenzyl, chlorophenylethyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is independently selected from the group consisting of hydrido andmethyl; wherein R⁵ is cyclopropylmethyl; wherein R⁷ is cyclohexylmethyl;and wherein R⁸ is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl,cyclohexylmethyl, allyl and vinyl.
 13. The composition of claim 12wherein R¹ is selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, benzyl, phenethyl, phenyl, fluorophenyl,chlorophenyl, trifluoromethylphenyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, fluorophenylpropyl, chlorobenzyl,chlorophenylethyl, chlorophenylpropyl, naphthyl, fluoronaphthyl,chloronaphthyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein x is zero or two; wherein R² is selectedfrom the group consisting of hydrido, methyl, ethyl and n-propyl;wherein R³ is selected from the group consisting of hydrido,cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is cyclopropylmethyl; whereinR⁷ is cyclohexylmethyl; and wherein R⁸ is selected from the groupconsisting of ethyl, n-propyl, n-butyl, isobutyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, allyl and vinyl.
 14. The composition ofclaim 13 wherein R¹ is selected from the group consisting of isopropyl,isobutyl, sec-butyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl,benzyl, fluorobenzyl, chlorobenzyl, naphthyl, fluoronaphthyl,chloronaphthyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereinR² is selected from the group consisting of hydrido, methyl, ethyl andphenyl; wherein R³ is selected from the group consisting of hydrido,cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is cyclopropylmethyl; wherein R⁷ iscyclohexylmethyl; and wherein R⁸ is selected from the group consistingof n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl allyl and vinyl.15. The composition of claim 14 wherein said renin-inhibiting compoundisN-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-α-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide.16. The composition of claim 14 wherein said renin-inhibiting compoundisN-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-α-[[(1,1-dimethylethyl)thio]methyl]benzenepropanamide.17. The composition of claim 14 wherein said renin-inhibiting compoundisN-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-αR*-[[1-oxo-3-(phenylsulfonyl)propyl]amino]cyclopropanepropanamide.18. A therapeutic method for treating hypertension, said methodcomprising administering to a hypertensive patient atherapeutically-effective amount of a compound of Formula I: ##STR45##wherein R¹ is selected from the group consisting of alkyl,trifluoromethyl, cycloalkyl, cycloalkylalkyl, aryl, haloaryl, aralkyland haloaralkyl; wherein x is a number selected from the groupconsisting of zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is selected from the group consisting of hydrido,cycloalkylalkyl, aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ isindependently selected from the group consisting of hydrido and methyl;wherein R⁵ is cyclopropylmethyl; wherein R⁷ is selected from the groupconsisting of alkyl, cycloalkylalkyl and aralkyl; wherein R⁸ is selectedfrom the group consisting of hydrido, alkyl, hydroxyalkyl, cycloalkyl,cycloalkylalkyl, alkenyl and haloalkenyl; and wherein any one of said R¹through R⁸ groups having a substitutable position may be substitutedwith one or more groups selected from the group consisting of alkyl,hydroxy, alkoxy and alkenyl.
 19. The method of claim 18 wherein R¹ isselected from the group consisting of alkyl, trifluoromethyl,cycloalkyl, cycloalkylalkyl, phenyl, halophenyl, phenylalkyl,halophenylalkyl, naphthyl, halonaphthyl, naphthylaklyl andhalonaphthylalkyl; wherein x is a number selected from the groupconsisting of zero, one and two; wherein R² is selected from the groupconsisting of hydrido and alkyl; wherein R³ is selected from the groupconsisting of hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from the group consisting of hydrido and methyl;wherein R⁵ is cyclopropylmethyl; wherein R⁷ is selected from the groupconsisting of cyclohexylmethyl and benzyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; and wherein R⁸ is selected from the group consisting of hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl.
 20. The method of claim 19 wherein R¹ is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl,chlorophenyl, trifluoromethylphenyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, fluorophenylpropyl, chlorobenzyl,chlorophenylethyl, chlorophenylpropyl, naphthyl, fluoronaphthyl,chloronaphthyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein x is a number selected from the groupconsisting of zero, one and two; wherein R² is selected from the groupconsisting of hydrido, methyl, ethyl and n-propyl; wherein R³ isselected from the group consisting of hydrido, cyclohexylmethyl, benzyl,phenylethyl, fluorobenzyl, fluorophenylethyl, chlorobenzyl,chlorophenylethyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyland chloronaphthylmethyl; wherein each of R⁴ and R⁶ is independentlyselected from the group consisting of hydrido and methyl; wherein R⁵ iscyclopropylmethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyland vinyl.
 21. The method of claim 20 wherein R¹ is selected from thegroup consisting of methyl, ethyl, n-propyl, isopropyl, benzyl,phenethyl, phenyl, fluorophenyl, chlorophenyl, trifluoromethylphenyl,benzyl, phenylethyl, phenylpropyl, fluorobenzyl, fluorophenylethyl,fluorophenylpropyl, chlorobenzyl, chlorophenylethyl, chlorophenylpropyl,naphthyl, fluoronaphthyl, chloronaphthyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein x is zero or two;wherein R² is selected from the group consisting of hydrido, methyl,ethyl and n-propyl; wherein R³ is selected from the group consisting ofhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is cyclopropylmethyl; wherein R⁷ is cyclohexylmethyl; and wherein R⁸ isselected from the group consisting of ethyl, n-propyl, n-butyl,isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl.22. The method of claim 21 wherein R¹ is selected from the groupconsisting of isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl,fluorophenyl, chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl,naphthyl, fluoronaphthyl, chloronaphthyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein R² is selected from the group consistingof hydrido, methyl, ethyl and phenyl; wherein R³ is selected from thegroup consisting of hydrido, cyclohexylmethyl, benzyl, fluorobenzyl,chlorobenzyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is hydrido; wherein R⁵ is cyclopropylmethyl; whereinR⁷ is cyclohexylmethyl; and wherein R⁸ is selected from the groupconsisting of n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyland vinyl.
 23. The method of claim 22 wherein said compound isN-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-α-[[(1,1-dimethylethyl)sulfonyl]methyl]benzenepropanamide.24. The method of claim 22 wherein said compound isN-[2-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-1R*-(cyclopropylmethyl)-2-oxoethyl]-α-[[(1,1-dimethylethyl)thio]methyl]benzenepropanamide.25. The method of claim 22 wherein said compound isN-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-αR*-[[1-oxo-3-(phenylsulfonyl)propyl]amino]cyclopropanepropanamide.